Accelerator mass spectrometry (AMS) is mainly used for detecting trace amounts of rare isotopes in samples. Generally, AMS is used for measuring the ratio of a rare isotope to an abundant isotope of the same element. For example, AMS can be used for detecting the rare isotope 14C in the presence of the much more abundant isotopes 12C and 13C. This can be used for determining the 14C/12C ratio for example for radio carbon dating of samples. An important advantage of AMS is the extreme sensitivity of the method. Features of AMS which contribute to its sensitivity include the suppression of molecular isobars and the use of detectors capable of detecting individual ions. An introduction to AMS and some of its applications is given in Yuangfang et al. (Pure & Appl. Chem. 66(2):305-334, 1994).
AMS can also be used in biomedical applications, in particular for drug development. For instance, AMS can be used for obtaining ADME (absorption, distribution, metabolism and excretion) parameters and/or other pharmacokinetic parameters of test compounds. Such studies are performed for example under the framework of the regulatory guidelines for metabolites in safety testing (MIST). For this purpose, generally a radiolabelled test compound is used. The most often used radiolabel is 14C. Some isotopes which are less frequently used as radiolabel include 10Be, 26Al, 41Ca, and 129I. The radiolabels can be used as tracer of the drug compound and metabolites thereof by virtue of the low natural abundance of these isotopes. They can also be used as tracer to show ADME behaviour of the particular atomic species itself, e.g. for 26Al and 41Ca. The extreme sensitivity of AMS (routinely 1 pg/mL or lower) allows for example for performing ADME studies, in particular mass balance studies, with low doses of a radiolabelled test compound. Using radiolabels has as disadvantage that it is costly to prepare test compounds in which a rare isotope is incorporated as radiolabel. Therefore, it would be beneficial if fluorine could be used as tracer in mass balance studies, because about 25% of the number of candidate drug compounds comprises fluorine groups. For certain platina comprising drugs, it would be useful if platina could be used as tracer.
Mutlib et al. mention that a mass balance study of fluorinated compounds was performed using 19F-NMR (nuclear magnetic resonance) (Chem. Res. Toxicol. 25(3):572-83, 2012). Generally, the sensitivity of 19F-NMR leaves room for improvement.
For samples containing an analyte compound labelled with 14C, AMS can for example provide a 14C/12C isotope ratio. This isotope ratio can be interpreted for example using the formula:K=(RM−RN)*F*(W/L)
where K is the concentration of analyte, RM is the isotope ratio of the sample, RN is the natural background isotope ratio, F is the carbon mass fraction in the sample (% C), W is the molecular weight of the analyte, and L is the specific molar activity of the analyte. L may indicate the average number of 14C per molecule. Also possible is the use of a calibration curve.
Accordingly, there is a desire for a method which allows for determining the quantity and/or concentration of an element in samples, in particular biological samples, with high sensitivity and without requiring the use of radiolabelled compounds. Also desired are accelerator mass spectrometry methods for analysing samples which have more flexibility as to the measured isotopes.
The present inventors have found that the above-mentioned desires can at least in part be met by using accelerator mass spectroscopy and measuring isotopes of two different elements.